More than 40 million women in the United States alone have entered their post-menopausal years. The life expectancy of a woman who has attained her last menstrual period is about 28 years and a study in 1982 indicated that about 75 to 85% of these women will develop symptoms of estrogen deficiency (Hammond et al., Fertilo Steril. 37(1): 5-25, 1982). One of the most common complaints of women following the commencement of ovarian failure is the "hot flash" or vasomotor symptom complex. This is characterized by a sudden onset of warmth generally lasting a few minutes, frequently evidenced by a visible red flush, and often accompanied by dizziness, nausea, headache, palpitations and diaphoresis. Adequate estrogen supplementation has been shown to provide relief to over 90% of these individuals.
There are many other post-menopausal symptoms of chronic hypoestrogenism, among the most serious is osteoporosis and ischemic heart disease. As many as 25% of women over 60 years old have documented spinal compression fractures as a result of osteoporosis related to estrogen deficiency and as many as 50% develop vertebral fractures by age 75.degree. A very large percentage of hip fractures in the elderly are attributable to osteoporosis. In 1980, a study carried out at the Mayo Clinic calculated the cost of hospital stays due to fractures at over one billion dollars per year (Gallagher et al., Clin. Ortho., 150:163, 1980).
Long-term estrogen replacement therapy is common for post-menopausal and other estrogen deficient women. It is, however, a more complicated issue for women having a uterus. Estrogen therapy has been associated with an increased incidence of endometrial cancer due to the continual "unopposed" estrogen-induced proliferation of the endometrium. Regular progestin administration inhibits the continual estrogen stimulation of the endometrium through an anti-proliferative effect and seems to reduce the rate of endometrial carcinoma in post-menopausal women receiving estrogen by several fold (Barbieri et al., Menopause Management, July/August 1992, 12-24). However, combination of estrogen and progestin frequently causes undesirable uterine bleeding which reduces the rate of patient compliance. There is also concern that the cardiovascular benefits of estrogen might be minimized by progestins (Speroff, Current Trends in Estrogen Replacement Therapy, 1986), Nevertheless, both sequential and concurrent estrogen plus progestin regimens are now predominately used in hormone replacement therapy for menopausal women with a uterus.degree. Notwithstanding the above, a woman without a uterus is adequately treated by estrogen alone.
Despite the well-established overall benefits of estrogen plus progestin replacement therapy for women having a uterus, the rate of patient compliance with this therapy suffers markedly because the treatment often requires women to endure side effects such as unpredictable bleeding and cyclotherapeutic withdrawal menstrual bleeding during a time in their lives when many women welcome cessation of menstrual bleeding as a normal occurance in menopause.degree. These side effects can be experienced during the entire treatment interval, which could be for the remainder of life. User satisfaction and compliance should all increase greatly if the principal benefits of the estrogen replacement therapy could be maintained while the estrogen-induced endometrial proliferation is inhibited without uterine bleeding.
The nature of the invention described here stems from the antiproliferative action of antiprogestin, i.e., its ability to inhibit endometrial proliferation during hormonal replacement therapy. This antiproliferative effect by antiprogestins per se has been noted (Gravanis et al., J Clin Endocrinol Metab, 60: 156, 1986; Wolf et al., Fertil Steril, 52:1055, 1989; Chualisz et al., Endocrinology, 129: 312, 1991), but the therapeutic value of this effect for hormone replacement therapy to menopausal women (which extends over a minimum interval of 20 days) has not been previously recognized.
The absence of thickening (proliferating) endometrium, as can be achieved with the administration of antiprogestins during extended estrogen replacement therapy, would decrease the risk of endometrial carcinoma (which is also decreased with progestins), but unlike that obtained with progestins would avoid unwanted vaginal bleeding that markedly reduces therapy compliance among postmenopausal women. Moreover, the addition of estrogen in combination with antiprogestin provides this advantage without negating the bone conserving efficacy derived from estrogen replacement therapy. These therapeutic advantages are achieved without any complications that accompany progestin administrations which in this invention is excluded in its entirety.
It is accordingly the object of this invention to provide a method of inhibiting the estrogen-induced proliferation of the endometrium without undesirable uterine bleeding and without sacrificing the advantageous properties of estrogen replacement therapy. This and other objects of the invention will become apparent to those of ordinary skill in the art from the following detailed description.